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Brain Sci. 2018, 8(4), 72; https://doi.org/10.3390/brainsci8040072

The GABAA Receptor α2 Subunit Activates a Neuronal TLR4 Signal in the Ventral Tegmental Area that Regulates Alcohol and Nicotine Abuse

1
Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
2
Neuropsychopharmacology Laboratory, Department of Psychiatry and Behavioral Sciences, Howard University College of Medicine, Washington, DC 20059, USA
3
Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
4
Laboratory for Neurodevelopment, Department of Anatomy, Howard University College of Medicine, Washington, DC 20059, USA
*
Author to whom correspondence should be addressed.
Received: 6 March 2018 / Revised: 4 April 2018 / Accepted: 18 April 2018 / Published: 21 April 2018
(This article belongs to the Special Issue Alcohol Induced Central Nervous System Damage)
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Abstract

Alcoholism initiates with episodes of excessive alcohol drinking, known as binge drinking, which is one form of excessive drinking (NIAAA Newsletter, 2004) that is related to impulsivity and anxiety (Ducci et al., 2007; Edenberg et al., 2004) and is also predictive of smoking status. The predisposition of non-alcohol exposed subjects to initiate binge drinking is controlled by neuroimmune signaling that includes an innately activated neuronal Toll-like receptor 4 (TLR4) signal. This signal also regulates cognitive impulsivity, a heritable trait that defines drug abuse initiation. However, the mechanism of signal activation, its function in dopaminergic (TH+) neurons within the reward circuitry implicated in drug-seeking behavior [viz. the ventral tegmental area (VTA)], and its contribution to nicotine co-abuse are still poorly understood. We report that the γ-aminobutyric acidA receptor (GABAAR) α2 subunit activates the TLR4 signal in neurons, culminating in the activation (phosphorylation/nuclear translocation) of cyclic AMP response element binding (CREB) but not NF-kB transcription factors and the upregulation of corticotropin-releasing factor (CRF) and tyrosine hydroxylase (TH). The signal is activated through α2/TLR4 interaction, as evidenced by co-immunoprecipitation, and it is present in the VTA from drug-untreated alcohol-preferring P rats. VTA infusion of neurotropic herpes simplex virus (HSV) vectors for α2 (pHSVsiLA2) or TLR4 (pHSVsiTLR4) but not scrambled (pHSVsiNC) siRNA inhibits signal activation and both binge alcohol drinking and nicotine sensitization, suggesting that the α2-activated TLR4 signal contributes to the regulation of both alcohol and nicotine abuse. View Full-Text
Keywords: TLR4 signal; PKA/CREB; CRF/TH; GABAA α2; HSV siRNA vectors; alcohol/nicotine abuse TLR4 signal; PKA/CREB; CRF/TH; GABAA α2; HSV siRNA vectors; alcohol/nicotine abuse
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Balan, I.; Warnock, K.T.; Puche, A.; Gondre-Lewis, M.C.; June, H.; Aurelian, L. The GABAA Receptor α2 Subunit Activates a Neuronal TLR4 Signal in the Ventral Tegmental Area that Regulates Alcohol and Nicotine Abuse. Brain Sci. 2018, 8, 72.

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